CANCER IS A DEVELOPMENTAL DISEASE. Human tumors, in particular pediatric tumors, often look like tissues that have not developed normally and whose growth has gone unchecked. In fact, recent studies have shown that many cancers arise because genetic and epigenetic aberrations in normal stem and progenitor cells lead to disordered development, resulting in the formation of malignant rather than normal tissues. For example, leukemia can arise when a mutation occurs in a normal blood stem cell, thus inducing formation of cancerous rather than normal blood. Analogous situations exist in other human tissues and their respective tumors. However, because of the relative rarity of normal stem cells in other parts of the body very little is yet known about how these stem cells go awry and create cancer.

SARCOMAS are bone and soft tissue tumors that predominantly affect younger individuals, including children, adolescents and young adults (<40 yrs). Unfortunately, these tumors are generally highly invasive and metastatic disease almost uniformly fatal. Although relatively uncommon, sarcomas account for a disproportionate number of years of life lost to cancer as a consequence of their presentation in younger patients. Unlike the vast majority of tumors that occur in older adults, sarcomas arise from mesenchymal rather than epithelial cells of origin. As such, the biology that underlies their initiation and progression is less well understood and intensive research efforts to elucidate the underpinnings of sarcoma development and pathophysiology are essential if new and better approaches to therapy are to be realized.

The Lawlor Lab focuses its research efforts on EWING SARCOMA, a rare but highly malignant tumor that primarily affects adolescents and young adults. Recent work from our lab and others suggests that Ewing sarcomas arise from stem cells of neural crest and/or mesodermal origin. Importantly, the Ewing sarcoma-associated oncogene EWS-FLI1 hijacks normal stem cell programs, critically disrupting normal genetic and epigenetic regulation and inducing cells to develop along a malignant rather than normal developmental path. In particular, disruption to epigenetic regulatory programs such as polycomb-mediated gene repression and DNA methylation are key pathogenic features downstream of EWS-FLI1 that drive the tumorigenic phenotype. Ongoing projects in the lab seek to elucidate the cellular and molecular basis for Ewing sarcoma initiation and progression and to test novel biologically-targeted agents that are directed against identified driver mutations and pathways.

Successful translation of laboratory discovery into clinical practice demands ongoing validation of results in “real life”. Therefore, for all our lab-based studies we test whether the results that we observe in our model systems are reflective of tumors in real patients. To achieve this we study sarcoma cell lines that were established from patients who donated pieces of their tumor to research. In addition, we work closely with other physicians and scientists at the University of Michigan and the Children’s Oncology Group to study fresh tumor tissues from patients who have been diagnosed with Ewing sarcoma. By committing to such a COLLABORATIVE AND CROSS-DISCIPLINARY RESEARCH PROGRAM we aim to make real and lasting contributions to sarcoma research and advance care for patients afflicted with these terrible tumors.